The purpose of these studies is to define the molecular mechanisms by which ligand occupancy of integrin receptors and other cell surface proteins alters the capacity of insulin-like growth factor-I (IGF-I) to stimulate smooth muscle cell (SMC) replication and migration. The studies will determine the role of ligand occupancy of the (_v133integrin in regulating recruitment of SHP-2 tyrosine phosphatase to the plasma membrane and subsequently to the IGF-I receptor. The tyrosine kinase that phosphorylates 133will be identified and how ligand occupancy of (_v133activates the kinase to alter SHP-2 recruitment will be analyzed. A protein that transfers SHP-2 to 133will be isolated and reagents prepared to determine how ECM protein binding to o_v63 stimulates this transfer protein to enhance SHP-2 recruitment. The molecular mechanism by which integrin receptor antagonists function to alter SHP-2 recruitment to IGF-IR will be further defined. The next series of studies will determine how failure to recruit SHP-2 to IGF-IR and to insulin receptor substrate 1 (IRS-1) leads to failure to activate downstream signaling components in the PI-3 and MAP kinase pathways. We will deter- mine whether other cell surface proteins that are involved in SHP-2 recruitment such as SHPS-1 directly alter IGF-IR activity and ability of IGF-IR to activate downstream signaling molecules such as Shc. We will deter- mine the role of SHP-2 transfer to p85 in regulating the activation of Rac-1 and Cdc-42. The necessity of SHP. 2 transfer to GTP exchange factors such as VAV-2 for MAP kinase activation will also be determined. Further studies will analyze the effects of altering ligand occupancy of SHPS-1 in controlling IGF-IR activation and SHP-2 recruitment to IGF-IR. SHPS-1 ligands will be isolated and their effects on these processes determined. The physiologic significance of the SHPS-l-integrin associated protein (lAP) interaction will be defined in several cell types by disrupting this interaction and determining the consequences for IGF-I signaling. The importance of this process for atherosclerotic lesion development will be studied directly in pigs. The SHPS-1/ lAP interaction will be inhibited and the effect on atherosclerotic lesion size determined. The results of these studies should help us to define molecular mechanisms by which the cell surface proteins function coordinately with IGF-IR to stimulate smooth muscle cell migration and replication and may suggest novel strategies for interfering with these processes to alter the progression of atherosclerosis.